CN104968332A - Pharmaceutical core-shell composite powder and processes for making the same - Google Patents

Abstract

A composite particle including a core with at least one carrier material; a fluidizing material layer on the surface of the core; and an outer layer comprising nanoparticles of an ingestible material distributed in at least one matrix-forming material. A process of making the composite particles includes the steps of dry coating carrier particles with a fluidizing material; preparing a suspension of nanoparticles of an ingestible material distributed in a matrix-forming material; and fluid bed coating the carrier particles with the suspension. The process and products provide quick dissolving composite particles which can be used for delivery of poorly water soluble ingestible materials in suitable dosage forms. The process of the invention reduces or prevents particle agglomeration during fabrication of the composite particles to enable delivery and quick redispersion of nanoparticles of the ingestible material from a dosage form.

Description

Medicinal core-shell composite powder and preparation method thereof

Background of invention

2. description of related art

The bioavailability of slightly water-soluble medicinal active ingredient is low, and this causes after being applied to patient, only have a small amount of medicine can be utilized by destination organization.Bioavailability difference is the significant problem run in research and development pharmaceutical composition.Poorly water soluble drugs and water solubility are less than the medicine of about 10mg/ml, tend to get rid of from gastrointestinal tract before being preferentially absorbed into circulation.

The dissolution rate of known granule medicament composition increases with the increase of surface area and the reduction of particle size.Therefore, the method preparing particulate pharmaceutical composition studied and made great efforts to control size and the size range of granule in pharmaceutical composition.Such as, used dry milling technique to reduce particle size and therefore to affect drug absorption.Although wet grinding is also useful reducing in particle size further, assemble/reunite or flocculate usually being limited to by low particle size about 10 microns (10,000nm).

Other technologies for the preparation of pharmaceutical composition comprise such as in emulsion polymerization process by drug loading in liposome or polymer.But, this kind of technology existing problems and limitation.Such as, the usually needs liposome soluble agents when preparing the liposome be applicable to.And unacceptable is usually need a large amount of liposomees or polymer to prepare unit dosage.In addition, the technology preparing this pharmaceutical composition is tending towards complicated.The major technical difficulty that emulsion polymerization meets with at the end of preparation technology, removes the poisonous pollutant of possibility as unreacted monomer or initiator.

Also need to prepare the dry type dosage form containing Nano medication granule.Simple spraying dry, lyophilization or lyophilization may cause the product poor, bulk density is low that flows.Interchangeable method forms core-shell composite particles, preferably uses thinner carrier granular.But thinner particle flow is not good, and its fluidisation is inevitable not good yet.Therefore, need to improve its flowing and fluidity method.

Yang et al. discloses several dry method treatment technology (Yang of the silica dioxide granule coating adhesion corn starch powder with different size, J., Sliva, A., Banerjee, A., Dave, R.N., andPfeffer, R., " Dry particle coating for improving the flowability of cohesivepowders (for improving the dry particle coating of mobility of adhesion powder); " Powder Technology, vol.158 (2005) 21-22).In some cases, the mobility by using the silica-coating of nano-scale to affect the corn starch of coating.

Chen et al., " Fluidization of Coated Group C Powders (fluidisation of the C group powder of coating); " AIChE Journal, vol.54 (2008) 104-121 discloses the method for the granule dry method coating adhesion Geldart C group powder with very small amount of nano-scale.It is said that dry method coating can improve the fluidity of powder.

Chen et al., " Fluidized bed film coating of cohesive Geldart group Cpowders (the fluid bed coating method of adhesion Geldart C group powder); " Powder Technology, vol.189 (2009) 466-480 discloses the method for dry method coating adhesion Geldart C group powder, to reduce Interaction of particles power and to improve the flowing situation of fine powder.On the fine powder of these precoatings, the polymer coating film of individual particle level is completed in commercially available spouted fluidized bed (MiniGlatt).

U.S. the patent No. 7276249 discloses method nano suspending liquid being sprayed into larger vector granule.It is said that the special based composition of the shellfish of coating has the pharmacokinetic property of improvement and supply/emptying (fasted) transmutability of reduction.Effective mean diameter of the special based composition granule of shellfish is close to about 2000nm.But the per unit weight product of these large carrier granulars has relatively low surface area, and this does not allow enough drug loadings, and make thicker coating become required, this can reduce the dissolution rate of active component.

The significant problem of art methods is the irreversible reunion of the coated medicament granule usually caused by the drying means of difference, and this can cause particle size much larger than 100 μm usually.The invention provides a kind of method of producing medicinal active ingredient (API) composite powder, it makes irreversible reunion and germination minimize and suitably obtains the redispersible nano-particle improving slightly water-soluble API stripping.

1. technical field

The present invention relates to the delivering compositions for oral delivery slightly water-soluble material.Particularly, the present invention relates to the particulate composition be made up of the composite particles of each non-agglomerated, it uses thin carrier granular to send medicine or the active substance of nano-scale with peroral dosage form, with and preparation method thereof.

Summary of the invention

First aspect, the present invention relates to composite particles, and it comprises the core with at least one carrier material, and comprises material that granule to be used sends as the medicinal active ingredient nano-particle skin as active substance and matrix formers.

Another aspect of the present invention relates to the method preparing medicinal composite particles, and it comprises the following steps: 1) apply thin carrier granular by nano-particle material dry method, to improve its fluidisation, and described nano-particle material normally non-active ingredient; 2) preparation is containing the stabilized nanoscale suspension of the nano-particle of active component; And 3) applying described carrier granular containing in the method for the compositions of the nano-particle of active component in described nano suspending liquid with comprising being included in.

Accompanying drawing explanation

Fig. 1 is the schematic diagram of an embodiment of the inventive method.

Fig. 2 is the schematic diagram of wet method agitated medium polishing used in the present invention.

Fig. 3 is the schematic diagram of the liquid solvent resistant sedimentation method used in the present invention.

Fig. 4 is the schematic diagram of melting emulsion process used in the present invention.

Fig. 5 depicts fluidized bed coating used in the present invention.

Fig. 6 is the schematic diagram of composite particles of the present invention.

Fig. 7 shows the particle size distribution of embodiment 1 several carrier granulars used.

Fig. 8 A-8B is with scanning electron microscopy (SEM) image of carrier particle surface after 1% nano silicon M5P (Fig. 8 A) and the coating of 0.17% nano silicon M5P (Fig. 8 B) dry method, as embodiment 7 implement.

Fig. 9 shows median particle diameter as the function for forming the amount of stabilizing agent according to the substrate of embodiment 10 emulsifying fenofibrate.

Figure 10 shows the median particle diameter of fenofibrate nanometer granule in nano suspending liquid as the function for the drug loading according to embodiment 10 emulsifying fenofibrate.

The SEM image of the composite particles of the PS-70 potato starch that Figure 11 display is prepared according to embodiment 12.

Figure 12 A-12B shows the SEM image of the composite particles of the L-89 lactose prepared according to embodiment 12.

Figure 13 is the graph of a relation that the reunion ratio of composite particles prepared according to embodiment 13 and substrate form between Polymer-supported.

Figure 14 is presented at and prepares in fenofibrate nanometer suspension according to embodiment 15, after adding sodium lauryl sulphate this granule of fluidized bed coating process nano suspending liquid before, the median particle diameter of fenofibrate nanometer granule is over time.

Figure 15 display is for three the different delivery systems used by drug delivery to animal according to embodiment 16, and in animal, the plasma concentration of API is as the function of time.

Figure 16 is the stripping curve figure of commercially available fenofibrate TriCore sheet and PS-70 composite sheet under different mixing speed in the dissolution test according to embodiment 17 (paddle speed).

Figure 17 to be presented in the dissolution test according to embodiment 18 in composite particles two kinds of different substrate and to form polymer to the impact of the stripping curve of composite particles.

Figure 18 to be presented in the dissolution test according to embodiment 19 size to the impact of the stripping curve of tablet.

Figure 19 be according in the dissolution test of embodiment 20 containing the stripping curve figure of the composite particles of griseofulvin and ibuprofen.

Figure 20 is presented at carrier granular and its caking in the dissolution test according to embodiment 21 and forms (cake formation) impact on the stripping curve of composite particles.

Figure 21 to be presented in the dissolution test according to embodiment 22 in composite particles two kinds of different dry-coated materials to the impact of the stripping curve of composite particles.

Figure 22 to be presented in the dissolution test according to embodiment 23 background media to the impact of the stripping curve of composite particles.

Figure 23 is presented at Polymer-supported in the dissolution test according to embodiment 24 in composite particles to the impact of the stripping curve of composite particles.

Figure 24 is presented in the dissolution test according to embodiment 25 in composite particles preparation process, adds the impact of mannitol on the stripping curve of composite particles.

Figure 25 to be presented in the dissolution test according to embodiment 26 support particles sizes to the impact of the stripping curve of composite particles.

The thick fine-graded particle size distribution of the L-89 composite particles determined is sieved in Figure 26 display according to embodiment 27.

Figure 27 is presented at the thick fine-graded stripping curve of L-89 composite particles in the dissolution test according to embodiment 27.

Figure 28 shows according to after embodiment 28 distributed test, from the particle size distribution of the fenofibrate after composite particles redispersion.

Figure 29 A-29B shows according to the step of the embodiment 28 SEM image of the composite particles of L-87 (29A) and PS-75 (29B) after redispersion in water.

Figure 30 is presented in the dissolution test according to embodiment 29 stripping curve of the various composite particles being pressed into sheet.

Figure 31 is presented in the dissolution test according to embodiment 34 stripping curve of two kinds of composite particles with different carriers granule.

Figure 32 is presented at the stripping curve of the composite particles adding mannitol in the dissolution test according to embodiment 35.

Figure 33 is presented at the stripping curve of composite particles PS-72 and L-86 in the dissolution test according to embodiment 36.

Figure 34 is presented at the stripping curve of the composite particles adding different material in the dissolution test according to embodiment 37.

Figure 35 is presented at the stripping curve of the composite particles forming material in the dissolution test according to embodiment 38 containing different substrates.

Figure 36 shows the size distribution curve of carrier granular before the fluidized bed coating process for determining reunion ratio and after coating.

The stripping that Figure 37 is presented at the tablet of different composite powder in the dissolution test carried out according to embodiment 41 is compared.

The stripping curve of composite powder and tablet that Figure 38 A shows L-87b & L-89 sample compares, the tablet of the L-87b & L-89 sample composite powder that Figure 38 B shows in SDS medium compares with the stripping curve of Tricor sheet, as according to embodiment 42 implement.

Figure 39 display as according to embodiment 43 the stripping in the buffer solution containing 10mM SDS solution of sample L-87b, CS-96 and Tricor sheet of implementing comparing.

The stripping curve of the tablet of Figure 40 show sample L-87b complex.Tablet dissolution rate is measured, to study the degraded of the tablet prepared according to embodiment 45 after storage several different time period.

The stripping curve that Figure 41 display has the capsule of the sample L-87b complex prepared according to embodiment 46 compares.

The detailed description of preferred embodiment

For illustrative purposes, by reference to multiple exemplary, principle of the present invention is described.Although certain embodiments of the present invention specifically describe in this article, those skilled in the art will easily recognize, same principle is equally applicable to and can adopts in other system and method.Before detailed description disclosed embodiment of the present invention, the present invention should be understood and do not applied the details being limited to shown any specific embodiment.In addition, term used herein be for illustration of object and unrestricted.And although some method is to be described with reference to the step of a definite sequence provided in this article, in many cases, these steps can be carried out with any order that it will be appreciated by those skilled in the art that.Therefore, new method is not limited to the specific arrangements of step disclosed herein.

Must be pointed out, unless the context clearly determines otherwise, herein and the singulative " (a) " used in appended claims, " one (an) " and " this (the) " comprise a plurality of indicant.In addition, term " " (or " "), " one or more " and " at least one " can exchange use in this article.Term " comprises (comprising) ", " comprising (including) ", " having (having) " and " by ... form (constructed from) " also can exchange use.

In first aspect, the present invention relates to preparation containing needing the method for composite particles of the composition sent with peroral dosage form.The method generally includes following steps: the nano suspending liquid 1) preparing composition to be delivered; With 2) with the compositions coated carrier granule comprising the material that described nano suspending liquid to be used is sent, to produce composite particles.Fig. 1 describes the exemplary of the inventive method.

In the step 1 of the method for Fig. 1, carrier granular is as required with the coating of coating material dry method, and object improves mobility and/or the reduction carrier granular reunion tendency of carrier granular.

Carrier granular can be made by absorbing human or animal safe any material, and is usually made up of pharmaceutically acceptable material.This kind of material normally pharmaceutical inert, cost is low, and can be crystallization or unbodied.Carrier granular is made up of inert material usually, and inert material is preferably hydrophilic, and more preferably solvable or swellable.Preferably, carrier granular to comprise in FDAGRAS (being commonly considered as safe) list and permits being used for one or more materials that are inner and/or medicinal usage, and usually sees in the list of usual excipients.The comprehensive list that can be used for the material of carrier granular is disclosed in United States Patent (USP) 6475523, and its full content is incorporated to by reference.Example as the applicable material of carrier granular comprises starch, modified starch, lactose, sucrose, polyhydric alcohol, cellulose, cellulose derivative as cellulose ethers and composition thereof, and described cellulose derivative at least comprises ethyl cellulose, methylcellulose and carboxymethyl cellulose; Such as, or they also can be class GRAS inorganic material, dicalcium phosphates.The instantiation of the carrier material be applicable to comprises potato starch, corn starch, wheaten starch, hydroxypropyl emthylcellulose, microcrystalline Cellulose, lactose, mannitol, sorbitol and other similar material.

The median particle size range of carrier granular is generally about 20 μm to about 200 μm, or about 20 μm to about 50 μm.In some embodiments, described carrier granular can be made up of multiple granule with narrow particle size distribution, because have wider distribution of sizes and the carrier granular comprising large or fine granule is more easily reunited in mixing and coating procedure simultaneously.Just can provide with regard to enough drug loading aspect in the coating, thinner carrier granular can provide maximum benefit.

Can select acceptable size range based on the width of particle size distribution, this width can be fixed in the enterprising professional etiquette of span, is defined as (d90-d10)/d50.Herein, d90 refers to the size of the volume distributed median of its lower existence 90%; Equally, d50 refers to the intermediate value that volume size distributes; And d10 refers to the size of the volume distributed median of its lower existence 10%.This span should be less than about 3, is more preferably less than about 2.Span up to 4 is also acceptable, and condition is the long-tail distribution that fine fraction or coarse fraction are not grown very much.Preferred d90 particle diameter is less than 300 μm, and d10 particle diameter is greater than 5 μm; Particularly, when d50 is less.

In the exemplary of Fig. 1, the fluidised material that coated carrier material adopts with the carrier granular forming coating can be such as nano SiO 2 particle.This coating material is used for improving the mobility of carrier granular, thus promotes the fluidisation such as in coating step subsequently, and the reunion of the carrier granular that simultaneously guarantee through storing, will occur after process and deep processing step minimizes.Also can adopt other nano-particle material, comprise, such as, there is relatively low dispersion surface energy as being less than 60mJ/m ²or be less than 40mJ/m ²such as there is the material of the median particle diameter of 5nm to 100nm.Preferably, described nano-particle be included in Food and Drug Administration GRAS (being usually considered to safe) list of materials on and permit being used for one or more materials that are inner and/or medicinal usage.Examples of materials for the suitable nano-particle of coated carrier granule comprises the nano-particle of silicon dioxide, aluminium oxide, titanium dioxide, white carbon black, calcium aluminosilicate, calcium silicates, magnesium silicate, potassium silicate, sodium silicate, sodium aluminosilicate, sodium aluminosilicate calcium, tricalcium silicate, aerosil, Talcum, ferrum oxide, other metal-oxide and composition thereof.

The nano SiO 2 particle used in the present invention can be any type, as silicon dioxide or the fumed silica of hydrophobic treatment.The example of silicon dioxide be applicable to comprise aerosil R972 silicon dioxide (winning wound (Evonik)), CAB-O-SIL EH-5 silicon dioxide (Cabot), CAB-O-SIL M-5P silicon dioxide (Cabot), CAB-O-SIL M-5DP silicon dioxide (Cabot), 200 drugmakers (winning wound), 200VV drugmaker (winning wound), 300 drugmakers (winning wound), OX-50 silicon dioxide (winning wound), COSM055 (catalyst and chemical industry company limited (Japan)), P-500 hydrophilic silicon oxides (catalyst and chemical industry company limited (Japan)) and TS530 silicon dioxide (Cabot).Generally, preferred specific surface area is greater than about 100m ²the fumed amorphous silica of/g.Usually, these forging amorphous silicas are produced by vapor-phase synthesis and carry out surface modification to change its hydrophobicity.In some embodiments, the silicon dioxide of more than one types can be combinationally used.Such as, silicon dioxide TS5 and silicon dioxide R972 can together with use, as long as they are acceptable for the medicinal application of expection.

Hydrophilic silicon oxides makes silicon dioxide drainage by hydrophobization process and obtains.In one embodiment, the hydrophobic treatment of described hydrophilic silicon oxides is by realizing with dichloro dimethanol silane treatment hydrophilic silicon oxides.Can use well known by persons skilled in the art can by silica modified any other suitable method for hydrophobic silica.Except improving flowing and fluidizing performance, hydrophobic silica also can contribute to the moistening of the API delaying coating and delay its initial release.

The weight content scope of the nano-particle material on carrier granular is 0.1% to 10% weight of the gross weight of the carrier granular of dry method coating.Alternatively, the nano-particle material from 0.1% to 1.5% or 1% to 5% weight can be used.It is believed that, the nano-particle material of high concentration (being namely far longer than 100% surface area coverage (SAC)) dry method coated carrier granule can be used, and leave silica dioxide granule available in fluidized bed coating process process.This excessive nano-particle material can from dry method coating carrier granular remove by force and fluidized bed coating process process subsequently dry method coated medicament composite powder.

Coating nano-particle material on the carrier particles causes the adhesion strength of carrier granular to reduce.That this thin carrier granular is normally adhered and not energy fluidizing.Although whether test carrier granule can the most reliable method of fluidisation be attempt making its fluidisation by reality, fluidity improved indirect indexes also can be reduced (AOR) or flow function coefficient (FFC) and increase and collect by angle of repose.Experience fluidized gas time fully reduce AOR or increase FFC and show subsequently coated particle fluidisation improvement any GRAS nano-particle material be all acceptable as coating material of the present invention.Can change the mobility of powder with nano-particle coating, and AOR estimates to be less than 45 degree, be more preferably less than 40 degree or even lower, and FFC may be increased to 6 or even higher, such as, be greater than 8.

The step 1 of the method for Fig. 1 is preferably carried out as dry method coating step.The device carrying out the dry method coating step of the step 1 of Fig. 1 can be any applicable device well known by persons skilled in the art.The device be applicable to includes but not limited to: Comil (U3Quadro Comil of QuadroPennsylvania, U.S.), LabRAM (Resodyne Minnesota, U.S.), magnetic secondary impingement coating machine (MAIC, Aveka Minnesota, U.S.), sound mixes machine and fluid energy mill (the Qualification Micronizer (micronizer) of FEM, SturtevantMassachusetts U.S.).Other examples of dry method coating equipment comprise heterozygosis device (Hybridizer) or Omnitex (Nara Machinary, Tokyo, Japan), mechanical fusion or latest edition are as Nobilta and Nanocular (HosokawaMicron Powder Systems, Osaka, Japan), θ designs product (Theta composer, TokujuCorporation, Tokyo, Japan), and to a certain extent, any high intensity mixer is such as with V-mixer (the PK Blend of stirring rod lab Blender, Patterson-Kelly, East Stroudsburg, PA) and (Cyclomix, Hosokawa Micron Powder Systems, Osaka, Japan).

The dry method of carrier granular applies and can complete within the relatively short time in the device being designed to carry out dry method coating.By contrast, some low-intensity blenders can be used, but it needs the longer processing time.In all cases, fairly large equipment will provide larger throughput rate, and significantly can not change the processing time.Those skilled in the art can develop applicable scale strategy.

Those skilled in the art are by considering that such as particle agglomeration and the carrier granular for coating provide the angle of repose of reduction (AOR) value to establish the operating condition of dry method coating.Particle agglomeration degree is determined by measuring the particle size applied in SEM image.Degree of aggregation also can use dispersive pressure titration Luo get and extra large Loews system (Rodos and Helos, Sympatec, Lawrenceville, NJ, USA) to estimate.The discussion of pressure titration is found in Han, X., Ghoroi, C, To, D., Chen, Y., Dav é, R., " Simultaneous micronization and surface modification for improvement offlow and dissolution ofdrug particles (micronization and surface modification are for improving flowing and the stripping of drug particles simultaneously) (2011)." international pharmaceutics periodical 415 volume 185-195 page, its full content is incorporated to by reference.The program determination AOR of ASTM D6393-99 can be used, " BulkSolids Characterization by CARR Indices (being characterized by the Loose Bodies of CARR index) ".Such as, when using Comil, impeller speed can be optimized reduce reunion (Fig. 3), because higher impeller speed can increase the agglomerate size of the carrier granular for dry method coating.

Product after dry method coating comprises the carrier granular of the coating that Fig. 1 schematically describes.Granule on surface is that several granule is thick.Nano-particle material on the surface of API-silica composite granules contributes to by introducing surface property (form is the surface roughness of nano-scale and the surface energy of the improvement) agglomerated improved minimized.Although carrier granular is adhered often, the carrier granular of coating has good mobility and can fluidisation.

The graphical analysis of the SEM image of the carrier granular that the surface area coverage (SAC) with the carrier granular of nano-particle material applies by dry method is estimated.In some embodiments, the scope of the SAC of the carrier granular of dry method coating is 15% to 100%, 25% to 100%, or 35% to 100%.In some embodiments, described SAC can be similar to 100%.

Other situations can not the fluidisation of carrier granular of fluidisation be that surface modification owing to applying based on dry method reduces caused by adhesion strength.Generally speaking, there is the adhesion strength that two factors facilitate intergranular captivation and this powder.First factor is usually by material surface energy or the surface characteristic of material that represented by Ha Meike constant.Generally speaking, when other conditions are identical, the Ha Meike constant of surface energy is lower or dispersive is lower will cause intergranular captivation to reduce, thus reduce adhesion strength.

Second factor is also surface characteristic, and it is the roughness in two interparticle contact faces.When every other condition is identical, very coarse, i.e. 100nm magnitude or higher roughness, or unusual light, namely atom smoothness or roughness are less than a few nanometer such as 5nm, and both of these case has can be called as the coarse higher interparticle attraction of nanometer than those; Namely such as use the surface roughness of atomic force microscope mensuration between 5 to 100 nanometers.More preferably, the surface roughness between 7-30 nanometer is adopted.Be 5-100 nanometer with particle diameter, more preferably 10-50 nanometer, and most preferably the nano-particle material of 20-50nm carries out dry method coating and can adhesion be caused due to the Nanoscale Surface roughness of giving to reduce.If the dispersive of the surface energy of nano-particle is lower (< 60mJ/m usually ², preferred < 40mJ/m ²), or be less than parent drugs powder, then may there is the additional effect that adhesion reduces.

Reduce because above-mentioned one or both factors listed cause that adhesion may occur, also can use the softer deformable material after mixing with lamellar character and smear (smear), replace using nano-particle to apply.This coating also causes the low dispersion surface energy of coated product.Therefore apply and also can be completed by following material, as magnesium stearate, stearic acid, leucine, aminoacid and being usually used in is sucked in application to be given the other materials of dispersion by hydrophobic and/or low adhesion material; See such as U.S. Patent number 6475523, wherein comprise the comprehensive list of surface active molecules, its disclosure is incorporated to by reference.Therefore, this kind of material will replace the discrete particle of silicon dioxide or nano-scale with deformable/flaky material.What adhesion declined is because lower dispersion surface energy causes, and may be also cause because surface roughness reduces, and it is that the space being filled in rough surface due to softer material produces more caused by smooth surface that surface roughness reduces.

The mobility of the carrier granular of dry method coating is by shear test FT4 powder rheometer (Freeman Technology, Tewkesbury, UK) and angle of repose (AOR) measure (Powder tester, Hosokawa Micron, Ltd., mm) assess.Stream function coefficient (FFC) as the index of powder flowbility, and is defined as the ratio of principal stress and unconfined yield strength.The direct stress of 3 kPas has been used to obtain FFC in this work.According to Shu Erci, FFC value can be divided into different grades (regime): i.e. FFC < 1, not flow; 1 < FFC < 2, adheres very much; 2 < FFC < 4, adhesion; 4 < FFC < 10, easily flow; And FFC > 10, free-flow.

With reference to the step 2 of figure 1, another step that can be used for the inventive method relates to the stabilized nanoscale suspension of preparation containing composition to be delivered.In step 2, parent material can comprise material to be delivered, solvent and one or more substrate formation material.Substrate forms material in this article sometimes referred to as " stabilizing agent ", because comprise substrate to form the nano suspending liquid that material tends to stablize material to be delivered in suspension, to guarantee that the nano suspending liquid of substances in liquids keeps enough stablizing in suspension, for storing and using in coating processes subsequently.In this sense, stable nano suspending liquid refers at the nano suspending liquid storing and do not experience between the operating period the remarkable precipitation of suspended material and/or the remarkable reunion of suspended material.

The granular materials of material to be delivered normally slightly water-soluble.In some embodiments, the present invention can use one or more in these materials.According to the needs of certain material, step 2 can comprise multiple step.Such as, in some cases, the particle diameter reducing material to be delivered before forming nano suspending liquid may be necessary.Step 2 always comprises and is suspended in form the step of nano suspending liquid in applicable fluent material by material to be delivered, and therefore the product of step 2 is stable nano suspending liquids, and the granule wherein containing material to be delivered is suspended in fluent material.

Any material to be delivered all can be suitable for the present invention, as long as it can provide with the form of nano-particle.The present invention is less than 10mg/ml for water solublity or is less than the material of 5mg/ml useful especially.Select amount of substance to be delivered to provide such nano-particle, that is, based on the volume of described nano suspending liquid, its amount of substance to be delivered contained is about 5w/v% to about 50w/v%, or about 15w/v% to about 40w/v%, or about 10w/v% to about 30w/v%.Material to be delivered in this article also referred to as active substance, and can comprise, such as medicinal active ingredient (API) or other materials be applicable to herein described in other place.

In some embodiments, may need to treat delivered substance before resuspending step and carry out pre-grinding or granule applicable in addition reduction process.Such as, the initial particle of this material may be too large for resuspending step, namely the scope of several millimeters or larger.

An example of pregrinding step adopts aeropulverizer.In an exemplary embodiment, with the fenofibrate (FNB) of fluid energy mill (Micronizer, Sturtevant, Hanover, MA) pre-grinding supply, to reduce to be in millimetre-sized initial particle.In fluid energy mill, accelerate FNB granule by compressed air stream.Due to the collision of pellet-pellet and granule-grinding locular wall, FNB granule is crushed into thinner fragment.Grinding pressure and supply pressure are set as 40psi and 45psi respectively.With the speed of about 12g/min, FNB granule is supplied to described fluid energy mill by screw feeder.After pre-grinding, FNB particle diameter is decreased to 90% of the median size (d50) of 11 μm and 34 μm by size (d90) (Rodos/Helos system, Sympatec, NJ, USA, dispersion method: 0.1 bar).

Solvent used in resuspending step can be aqueous solvent, and as water, deionized water (DI) or distilled water, and when drug material is water-soluble hardly, this kind of aqueous solvent is applicable.In some embodiments, organic solvent such as acetone or alcohol is applicable to preparation suspension of the present invention, as long as medicine does not have considerable dissolubility in solvent used.Particularly advantageous solvent is safe and/or through ratifying confession people and/or animals consuming material when taking in.Other examples of spendable solvent comprise: the tert-butyl alcohol (TBA), oxolane (THF), dimethyl sulfoxine (DMSO), dichloromethane, dimethyl formamide (DMF), methanol and composition thereof.

Substrate of the present invention forms the object that material is used for stabilized nanoscale suspension.Described substrate forms material can comprise polymer and optionally surfactant.Some examples of suitable substrate formation polymer comprise the hydroxypropyl cellulose (HPC) of various grade, hydroxypropyl emthylcellulose (HPMC), poly-(vinyl alcohol) (PVA), PVP (PVP), PVP-K360, PVP-K30, ammonio methacrylate copolymer, ethyl cellulose, polyvidone S630, hydroxy methocel, hydroxyethyl-cellulose (HEC), methylcellulose (MC), sanlose, 30 POVIDONE K 30 BP/USP 15, Radix Acaciae senegalis and combination thereof.

The example of suitable surfactant comprises sodium lauryl sulphate (SDS), dioctylsulfosuccinat (DOSS), non-ionic ethylene oxide/epoxy propane copolymer, pluronic F-68 (PF-68, PLURONICS F87), cetab (CTAB), pluronic F-127 (PF-127, poloxamer188), Tween 80 (T-80, polyethylene sorbitan ester), sodium alginate (SA), polysorbas20, lecithin, sodium lauryl sulfate, monoleate, monolaurate, monostearate, stearyl alcohol (stearylic alcohol), octadecanol (cetostearylic alcohol), alevaire, Cremaphor EL is as polyoxyethylene castor oil and composition thereof.Surfactant preferred nonionic surfactants used in nano suspending liquid.

The combination that one or more surfactants and one or more substrate form polymer is easy to cause suspension surface tension force to reduce and viscosity increase.Surface tension reduction can increase nucleation rate, and therefore makes particle diameter reduce.Equally, viscosity increase can reduce collision frequency, and because this reducing quality transmission (mass transfer) speed from solution to the solid-liquid interface of growth.This tends to reduce reunites, but also may increase the sedimentation time.Polymer and surfactant reduce the surface energy at interface in the absorption of the solid interface of growth and suppress germination.Therefore, the existence that substrate suitable in solution forms material prevents a large amount of germinations, and this makes nanoparticles stable in suspension, thus to anti-agglomeration.

The scope of the described substrate formation material causing comprising is 5w/v%-50w/v% or 10w/v%-35w/v% or the 15w/v%-30w/v% of described nano suspending liquid cumulative volume by the amount of step 2 mesostroma formation material.In some embodiments, substrate forms material also can comprise matrix enhancement material, as mannitol lactose, sucrose, trehalose, Ai Wei element PH101, Inutec SP1, microcrystalline Cellulose, sorbitol, dextrose, Pharmatose, maltodextrin glucose (maltodextrose), xylitol, saccharide and other polyalcohols.

The effect of matrix enhancement material is the formation strengthening substrate, is bonded to layer in carrier particle surface to make API nano-particle.Add mannitol and also to cause dissolving when starting API nano-particle from composite particles stripping quickly, thus make caking start to be formed before discharge more drug.

In the exemplary of Fig. 1, step 2 comprises the sub-step of agitated medium grinding, grinds also referred to as wet method agitated medium.Fig. 2 depicts the schematic diagram of applicable agitated medium grinding technics.In the embodiment of fig. 2, the device for agitated medium grinding is recirculation flour mill MicroCer (Netzsch, Exton, PA, USA), and it is equipped with pin rotor.The volume of grinding chamber is 80ml, and its liner has zirconium oxide.Grinding chamber and stirred vessel are all connected to external refrigeration equipment (M1-.25A-11HFX, Advantage, Greenwood, IN, USA), with the heat produced in the milled processed process that dissipates.Pre-suspension is preparation like this, and the substrate namely by adding aequum forms material to deionized water solution, and mixing is until pre-uniform suspension, is then added in pre-suspension by material to be delivered and stirs simultaneously.In agitated medium process of lapping, suspension circulates between medium grinder and stirred vessel.Sample in grinding chamber exit.Grinding suitable condition for agitated medium is: the Filled Dielectrics ratio of grinding chamber is 62.5% (v/v), suspension flow velocity is 120ml/min (ml/min), the rotary speed of grinding rotor is 3200rpm, and this is equivalent to the maximum stirring tip speed of 11.8m/s (meter per second).

By monitoring the progress of agitated medium grinding to particle size sampling.Small sample can be fetched from the sample exit port of grinding chamber.The dilution of sample deionized water is used for particle size determination.Particle size distribution is measured with laser diffraction apparatus LS 13 320 (Coulter Beckman, Brea, CA).Polarization intensity differential scattering (PIDS) can be used to cover water optics model.Mie theory software can be used by adopting suitable refractive index (RI) value, such as fenofibrate particles 1.55 and calculate particle size distribution for measure medium (water) 1.33.

In some embodiments, the step 2 of Fig. 1 can also by using the liquid solvent resistant sedimentation method (LASP) in the T-shaped blender of ultrasound wave driving.Except T-shaped blender, other device also can be used for LASP subprocess.Example comprises mixing chamber, Y type blender, static mixer and RPB.Described LASP can provide some advantages, such as relatively fast, less energy consumption and cost efficient.In addition, this precipitation routes provides motility by the physicochemical properties using substrate and form material manipulation solution and solvent resistant phase for controlling granular size and distribution.

In the embodiment that Fig. 3 describes, T-shaped blender can strengthen microcosmic mixing.In T-shaped blender, API suspension flow and solvent resistant stream collide in mixed zone, at short notice, in described blender, just reach high supersaturation.High oversaturated generation can be further improved by adopting ultrasonic Treatment.Suppose that the cavitation produced by supersound process makes because following multiple reason causes forming nano-particle: (i) sets up in system inside the turbulent-flow conditions guaranteeing effectively mixing; (ii) organic solution of medicine is atomized into superfine drop being added in stabilizing agent aqueous solvent process; (iii) reunion of the new granule formed is reduced.

T-shaped blender used in the present embodiment has 2 inches of ID (internal diameter) × 2 inch long cylindrical Delrin (delrin) (from McMaster Carr, Santa Fe Springs, CA, USA).Get out the side opening that two OD (external diameter) are 0.0787 inch, become the entrance for solvent resistant (substrate be dissolved in DI water forms material) and organic solution (API in acetone).Also getting out the T-shaped mixer outlet of 0.1875 inch of external diameter, discharging for making the stream of solvent resistant and solution.Get out ultrasonic bag (pocket) for introducing ultrasound probe (Omni-ruptor 250, Omni International Inc., USA), it has the internal diameter of 0.5 inch.The ultrasound wave without special seal is used to carry out containing fluid.T-shaped blender open design is adaptive ultrasound probe, to guarantee best fluid-nozzle contact.Use HPLC pump (Model CP, Laballiance, PA, USA), by rustless steel nozzle (0.01 inch of ID), solvent and solvent resistant solution are delivered to T-shaped blender with the flow pump of 16.5-17 and 55.1ml/min respectively.See Fig. 3.

In T mixed process, solvent-proof temperature is remained on 1 DEG C.API solution is remained on room temperature.Batch is 80ml.In 80ml suspension, there are 10ml API solution and 70ml solvent resistant.Before precipitation, 20ml solvent resistant is put into collecting chamber and is used for quenching, and extract remaining 50ml out in T mixed process.Collecting chamber to be remained in ultra sonic bath (VWR-B2500A-MTH, ultrasonic cleaner, International, West Chester, PA) and continue ultrasonic Treatment during T-mixing subprocess.Then, with 25 μm of sieve filtering suspension liquids with the possible block observed after discarding precipitation.

In some other embodiments, the step 2 of Fig. 1 also can use melting breast sub-processes, and its schematic diagram is depicted in Fig. 4.Melting breast sub-processes can comprise the following steps.First, micronized particle and substrate are formed dispersion of materials in water, and suspension is heated to the temperature of more than the fusing point of material to be delivered.For guaranteeing complete melting and reducing the viscosity of fused mass, the temperature of the fusing point at least 10 DEG C higher than material to be delivered should be reached.Gentle agitation is carried out with magnetic stirrer in heating process.The second, with ultrasound probe (Vibra Cell VC 750, Sonics & Materials, Inc., Newtown, CT) with the intensity emulsifying reasonable time be applicable to.In emulsifying step, by suspension keep at high temperature (10-15 DEG C+Tm) to avoid fused mass to solidify.3rd, hot Emulsion is cooled fast, until API suspension reaches the temperature lower than 10 DEG C in the temperature chamber (NESLAB TRE 10, Thermo Electron Corporation, Newington, NH) of 4 DEG C.

The stability of selection to nano suspending liquid that substrate forms material (be generally polymer and optionally surfactant) is important.Ultra sonic bath can be used to select effective polymer and/or surfactant and its concentration for predetermined substance to be delivered.In ultrasonication, by substance dissolves to be delivered in acetone to form clear solution.Being stirred by magnetic makes substrate form material dissolves in DI water.The solution of material to be delivered is added into fast substrate in the ultrasonication of ultra sonic bath (VWR-B2500A-MTH, ultrasonic cleaner, VWR International, West Chester, PA) to be formed in the aqueous solution of material.The persistent period of supersound process can be 1 minute, and it comprises the interpolation time of initial solvent.Then, filtering suspension liquids are sieved to discard possible block with 25 μm.Suspension is at room temperature preserved 2 days.Granularmetric analysis is carried out to those suspensions still suspended after 2 days.Before granularmetric analysis, use turbine mixer or magnetic stirrer that suspension is suitably mixed 1 minute.Available laser diffraction Size Analyzer Beckmann Coulter LS 13-320 (Miami, FL, USA) carrys out size up.The substrate causing minimal particle to grow and to precipitate forms material and concentration can be used for the present invention.

To monitor the particle size in suspension as LS 13320 (Coulter Beckman, Inc., Brea, CA) by laser diffraction apparatus.In addition, granule morphology evaluation is carried out by scanning electron microscope (LEO 1530SVMP, Carl Zeiss, Peabody, MA).Use Inlens detector can obtain digital picture under the accelerating potential of 2 kilovolts.Subsequently the sample of dilution is deployed into clean silicon wafer to prepare SEM sample by diluted suspension in deionized water.Then, under dustless condition in exsiccator this wafer dry, and with carbon coating in BAL-TEC MED 020 (BAL-TECAG, Balzers, Switzerland), with the charge effect during being reduced to picture.

The product of the step 2 of Fig. 1 is the suspension containing material to be delivered, and it forms material by substrate and stablizes.Stable suspension is considered to the suspension experiencing minimal particle reunion.By at room temperature this suspension being stored the stability evaluating suspension over 2 days.Before and after 2 day storage life, granule is sampled.If do not have obvious particle diameter to increase, then this suspension is considered to stable.

In step 3 of figure 1, fluidized bed coating is such as used the suspension of step 2 to be used for the carrier granular of coating step 1.The more detailed schematic diagram of suitable fluidized bed coating is shown in Figure 5.In the method for Fig. 5, the carrier granular of coating is supplied to fluidized bed coating process room.The air of heating is blown into make the particles circulating of these indoor to this room.Then the suspension pump comprising material to be delivered is delivered to nozzle, atomizing suspension is sprayed into fluidized bed coating process room by this nozzle.Fluidized bed coating process has come by top spraying, bottom spraying, tangential spraying or other suitable method any.The Mini-Glatt9550 manufactured by the Glatt of New Jersey can be used as the applicable device of fluidized bed coating.Mini-Glatt9550 is shown in Fig. 2, is configured to top spray fluidized bed coating process.

After small droplet, sprayed into fluidized bed coating process room.Solvent is after suspension evaporation, and small droplet is attached to carrier particle surface, and forms the layer of the granule comprising material to be delivered and substrate formation material.

In some embodiments, it is applicable that a small amount of silicon dioxide (it can be stable silicon dioxide) is mixed into fluidized bed coating process room, can periodic intervals be mixed in some cases.Silicon dioxide can play the effect reducing or prevent to reunite in fluidized bed coating process process.The median particle size range being applicable to the silicon dioxide of this object can be 100nm to 500nm, and amorphous silica sol is preferred.Can use known method (see such as " the Controlled growthof monodisperse silica spheres in the micron size range controlled growth of monodisperse silica microspheres (in the micron magnitude range); " Journal of Colloid and Interface Science, 26 volumes, 1st edition, January nineteen sixty-eight, 62-69 page, Werner arthur Fink, ErnstBohn doi:10.1016/0021-9797 (68) 90272-5) prepare the silica dioxide granule that diameter is 180nm or larger.The silicon dioxide that this step uses is different from the silicon dioxide for coated carrier granule, and it has less median particle diameter.The silicon dioxide used in this step is preferably stable, thus to anti-agglomeration.Routine techniques can be used for stabilized chlorine silicon grain, comprises with NaOH or by regulating the pH of silicon dioxde solution to increase ionic strength.

The silicon dioxide that can be used for mixing with the spraying of API nano suspending liquid can be selected from aerosil R972P (or pharmaceutical grade R972P), and other example comprise CAB-O-SIL EH-5 silicon dioxide (Cabot), CAB-O-SIL M-5P silicon dioxide (Cabot), CAB-O-SIL M-5DP silicon dioxide (Cabot), 200 pharmacy (winning wound), 200VV pharmacy (winning wound), 300 pharmacy (winning wound).

The drop size of spray suspension liquid is very important for the quality of fluidized bed coating process performance and final composite particles.Larger drop size may bring difficulty for drying, and causes the formation of undesirable aggregate subsequently.On the other hand, less drop size may due to drop arrive dry method coating carrier particle surface before solvent rapid evaporation and cause material damage to be delivered.Can use Malvern Spraytec system (Malvern Instrument Inc., UK) on nozzle, measure the drop size of spray suspension liquid, this nozzle has the aperture of 0.5mm, is positioned at distance laser beam 15cm and the position of Range Focusing mirror 15cm.

The drop size of spray suspension liquid can be subject to the impact of polymer concentration in suspension.Average droplet size is with the non-linear increase of polymer concentration, because the suspension containing high polymer concentration is easy to form high viscosity material and need more energy to be atomized into small droplet.Therefore, in suspension, high polymer concentration (thus full-bodied suspension) may require that higher energy input is to be atomized this solution, to produce enough little drop.

Preferred drop size is less than the size of carrier granular.In some embodiments, the scope of preferred drop size is 5 μm to 15 μm, or 7 μm to 12 μm.In addition, in some embodiments, guarantee that the drop of spray suspension liquid has narrow droplets size distribution to promote that the formation of single-size layer is favourable.The ratio of preferred d90-d10 and d50 is equal to or less than 2.Wider distribution can cause the spraying dry of fine fraction, and coarse component can promote to reunite.

The spray rate of spraying API nano suspending liquid also can affect fluidized bed coating process performance.Polymer concentration lower in API nano suspending liquid can allow to use higher spray rate.But spray rate must balance with fluidization rate.Can fluidization rate be selected, powder can be fully fluidised.High spray rate can cause the wet condition that can cause reunion, and low spray rate can cause causing spray-dired drying condition.Spray rate may be relevant with droplets size distribution, and droplets size distribution usually with spray rate linear change and with square being inversely proportional to of pressure.

Be 1cm/s-10cm/s or preferred 3-7cm/s for reducing in fluidized bed coating process process the suitable fluidizing velocity of reuniting in Mini-Glatt device.Should spray rate be controlled, the environmental condition of fluid bed inside is in the scope of 25-40%RH and 25-30 DEG C.

According to the scale of fluid bed, the flow velocity (product of surperficial gas speed and bed sectional area) of fluidisation, spray rate and atomizing pressure can be controlled, to keep surperficial gas speed and droplets size distribution in the scope expected, still keep environmental condition in bed in the limit of expectation simultaneously.

The carrier granular of reduced size may need lower fluidizing velocity than large carrier granular.Spendable fluidisation flow velocity during it reducing fluidized bed coating process.In addition, spray rate must be reduced with the change of compensation current speed.This finally can cause the significantly longer processing time.

In some embodiments, intermittent spray technology can be adopted to complete the spraying of suspension.Intermittent spray is by the periodically sprinkle polymer solution regular hour, then stops the sprinkling regular hour to realize, and some dryings can occur during wherein stopping spraying.Applicable intermittent spray cycle can adopt 120 seconds spraying phases and 120 seconds non-ejection phases.Other spraying phase scope be applicable to can be the non-ejection phase of 20 seconds to 3 minutes and same 20 seconds to 3 minutes, does not need the spraying phase identical with the non-spraying phase.

Namely suspension drop in the dry-coated carrier particle surface covered forms the layer of material to be delivered and substrate formation material after solvent evaporation.The end product of the inventive method is composite particles, as shown in Figure 6.Composite particles has the core derived by carrier granular.Carrier particle surface exists the partial or complete layer of material to improve the mobility of carrier granular such as silicon dioxide.In the outside of this layer, there is the layer be combined to form being formed the granule of material by material to be delivered and substrate.

Outer layer material does not need the whole surface covering carrier granular.The surface area coverage (SAC) with the carrier granular of outer field coating can in the scope of 15% to 100%, in the scope of 25% to 100%, or in the scope of 35% to 100%.In some embodiments, SAC can close to 100%, and in order to provide the maximum load of material to be delivered, usually higher SAC can be applicable.Outer field thickness range is about 1 μm to about 10 μm, or about 2 μm to about 7 μm, or about 2 μm to about 5 μm.Material to be delivered can be any applicable material.In some embodiments, material to be delivered is the material showing slightly water-soluble.Exemplary material be medicinal active ingredient (API ' s), supplementary, vitamin, mineral or other Absorbable rod material.Exemplary API comprises fenofibrate, griseofulvin, ibuprofen, itraconazole, naproxen, sulfamethoxazole, Phenylbutazone, Celogen Az, danazol, albendazole, nifedipine, cilostazol, ketoconazole, budesonide (Budenoside), loviride, glimepiride, xenyl dimethyl dicarboxylic acids, Digitoxin, paclitaxel, meticortelone acetic acid, hydrocortisone acetate and any suitable mixture thereof.

The present invention can comprise with for the protection of, reduce the optional step that granule adhesion and/or the optional layer of controlled release apply composite particles further.If necessary, the method for any routine and/or material can be used for this optional layer coating composite particles in the present invention.The thickness range of optional layer is 1 μm to 5 μm, or 1 μm to 3 μm.

Composite particles can discharge rapidly material to be delivered from described granule.Can by carrying out to dispersion granule in a solvent the dispersion that dimensional measurement carrys out evaluating combined granule.Such as, 100mg composite particles to be added in bottle in 8mlDI water.Bottle was slowly mixed in hand 30 seconds.Then bottle is made to keep static 2 minutes.By the distribution of sizes of the granule in determination of laser diffraction solution.This composite particles can in 10 minutes, preferably in 5 minutes, most preferably discharge in 2 minutes at least 90% the granule containing material to be delivered.

Composite particles of the present invention design is used for sending Absorbable rod material, such as medicinal active ingredient (API), supplementary, vitamin or other Absorbable rod material and composition thereof.Composite particles can use like this, or can be mixed with any applicable dosage form, such as tablet, hard capsule, soft capsule, chewable tablet, medicated bag or pouch, Orally disintegrating tablet or lozenge, film (wafer) and pill.Also composite particles can be mixed in other Absorbable rod material such as gel or chewing gum.

Useful multi-medicament material implements the present invention.Drug substance preferably exists in a substantially pure form.Medicine can be indissoluble, but must dissolve at least one liquid medium." indissoluble (poorlysoluble) " refers to that this medicine dissolubility is in an aqueous medium less than about 10mg/ml, is preferably less than about 1mg/ml.

Suitable drug substance can be selected from known various kinds of drug, comprising: such as analgesic, antibiotic medicine, anthelmintic, antiarrhythmics, antibiotic (comprising penicillins), anticoagulant, antidepressants, antidiabetic drug, antuepileptic, antihistaminic, antihypertensive, muscarine antagonist, antimycobacterial drug, antineoplastic agent, immunosuppressant, antithyroid drug, antiviral agent, anxiety tranquilizer (sleeping pill and tranquilizer), astringent, receptor,β blocker, blood products and substitute, heart inotropic agent, contrast agent, corticosteroid, cough medicine (eliminating the phlegm and mucolytic), diagnostic agent, diagnostic imaging agent, diuretic, dopaminergic (anti-parkinson agent), hemorrhage, immunizing agent, lipid regulating agent, muscle relaxant, parasympathomimetic agent, parathyroid gland calcitonin and diphosphonate, prostaglandin, radioactivity medicine, gonadal hormone (comprising steroid), anti-allergic agent, analeptic and anoretics, sympathomimetic, thyroid, vasodilation and xanthine.Preferred drug substance comprises for those of oral administration.The description of this kind of medicine is found in Martindale's Extra Pharmacopoeia Martindale (Martindale, the extraPharmacopoeia, the 29 edition with the various list in each class, Pharmaceutical Press, London, 1989), its disclosure is incorporated to herein in full by reference with it.Described drug substance is commercially available and/or prepare by technology known in the art.

Composite particles can contain the active substance of such as about 0.01-50wt% or 0.1-40wt% or material to be delivered, the substrate of about 0.5-4wt% forms material, about 0.05-is about the surfactant of 0.3wt%, the fluidised material of about 1.0-3.0wt%, and the carrier material of about 68-91wt%.

Embodiment

Embodiment 1

With nano SiO 2 particle (CAB-O- m5P hydrophilic silicon oxides and AerosilR972P-hydrophobic silica) dry method coating potato starch (PS).Measured the particle size distribution of carrier material by laser diffraction (Helos, Sympathec) under the dispersion pressure of 0.5bar.Fig. 7 shows the particle size distribution of carrier granular.The parent material used in the present embodiment and following examples is listed in table 1.

Table 1-dry method coating material

In V-mixer (the Blend Master of Patterson Kelley), potato starch powder and nano SiO 2 particle are mixed.V-mixer 5 minutes are run with the speed of 27rpm under the fill level of about 40%.Dry method coating is carried out with magnetic secondary impingement coating (MAIC) method or Comil.Device for MAIC is that inventor is homemade.By in 30g potato starch and nano SiO 2 particle adding apparatus, Magnet is 2: 1 with powder ratio, and voltage is about 60V, 36Hz, carries out 10 minutes.

About Comil, it is the U3QUADRO COMIL (Quadro) of screen size 457 μm.Impeller goes in ring with rotating speed 2600rpm.With the feed rate screw feeder of 20g/min, 30g potato starch and nano SiO 2 particle are added in Comil.Apply only for single treatment by the dry method of Comil.

Measure the flowing property of the carrier granular of dry method coating.Flowing function coefficient (FFC) is measured by powder flowbility tester (Powder Rheometer) FT4 of Freeman Technology.Angle of repose (AoR) is measured by the powder property tester of Hosokawa.Determine that 0.17%M5P on potato starch and 100% theoretical surface amass coverage rate (SAC) relevant.The flowing property of the potato starch of dry method coating is given in table 2.

The flowing property of the carrier granular of table 2-dry method coating

For potato starch, MAIC and Comil all produces excellent flowing property.With the surface (Fig. 8 A-8B) of nano silicon uniform fold PS.Higher silica brings good PS surface coverage (Fig. 8 A has 1%M5P relative to Fig. 8 B, has 0.17% silicon dioxide)

Embodiment 2

With nano SiO 2 particle (CAB-O- m5P-hydrophilic silicon oxides) dry method coating corn starch (CS).Diameter of carrier and nano silicon particle diameter is given in table 1.

In V-shaped blender (the Blend Master of Patterson Kelley), corn starch powder and nano SiO 2 particle are mixed.V-mixer 5 minutes are run with the speed of 27rpm under the fill level of about 40%.Dry method coating is carried out in Comil.Comil is the U3QUADRO COMIL (Quadro) of screen size 457 μm and 152 μm.Impeller goes in ring with rotating speed 1300rpm.With the feed rate screw feeder of 5g/min or 10g/min, the mixture of corn starch and nano SiO 2 particle is added in Comil.Single treatment or twice process is carried out with the dry method coating of Comil.The flowing property of the corn starch of dry method coating is given in table 3.

The flowing property of the carrier granular of table 3-dry method coating

Embodiment 3

With nano SiO 2 particle (CAB-O- m5P, hydrophilic silicon oxides) dry method coating corn starch (CS).Diameter of carrier and nano silicon particle diameter is given in table 1.

In V-mixer (the Blend Master of Patterson Kelley), corn starch powder and nano SiO 2 particle are mixed.V-mixer 5 minutes are run with the speed of 27rpm under the fill level of about 40%.Dry method coating is carried out in LabRam (Resodyn Acoustic Mixers, Inc).With the 50g mixture of carrier granular and nano SiO 2 particle be carry out applying by the dry method of LabRam in the LabRam of 50ml at tankage size.Fill level is about 15%.LabRam service condition and the flowing property of the corn starch of dry method coating is given in table 4 and table 5.

The dry method coating of table 4-corn starch

The intensity (under same acceleration) of batch size and LabRam can affect AoR.The raising observing both all causes AoR to reduce (mobility is better).See table 5, higher intensity causes the shear stress of collision stronger between host grain (host particle) and objective granule (guest particle)/higher, which improves coating quality.Use larger batch size to improve mobility, because at one time, will larger granule and the collision of granule be had.

The dry method coating of table 5-corn starch

Embodiment 4

With nano SiO 2 particle (CAB-O- m5P, hydrophilic silicon oxides) dry method coating lactose (GranuLac 200) i.e. carrier material.Diameter of carrier and nano silicon particle diameter is given in table 1.

In V-mixer (the Blend Master of Patterson Kelley), lactose powder and nano SiO 2 particle are mixed.V-mixer 5 minutes are run with the speed of 27rpm under the fill level of about 40%.Dry method coating is carried out in LabRam (Resodyn Acoustic Mixers, Inc).Carry out applying by the dry method of LabRam in LabRam with the 150g mixture of carrier granular and nano SiO 2 particle.LabRam service condition and the flowing property of the corn starch of dry method coating is given in table 6.

The dry method coating of table 6-corn starch

Embodiment 5

To the fenofibrate material pre-grinding received in fluid energy mill (micronizer, Sturtevant, Hanover, MA), to reduce the original API particle diameter for humid medium grinding.In fluid energy mill, by compressed air stream and due to the shock of particles versus particle and with the collision of grinding locular wall to Particle Acceleration, grain breakage becomes thinner fragment.In an experiment, grinding pressure is arranged to 40psi, uses screw feeder to realize the feed rate of about 12g/min.After stream can grind, fenofibrate particle diameter is down to d50=16 μm and d90=29 μm.Table 7 lists some materials used in the present embodiment and following examples.

Table 7-is used for the material of wet agitated medium grinding

Embodiment 6

The wet agitated medium grinding of fenofibrate is carried out in recirculation mill MicroCer (Netzsch, Exton, PA) being equipped with pin rotor (pin rotor).The volume of grinding chamber is 80ml, and liner has zirconium oxide.Grinding chamber and stirred vessel all connect with external refrigeration equipment (M1-.25A-11HFX, Advantage, Greenwood, IN), to disperse the heat produced in process of lapping.Stabilizing zirconia is carried out with the yttrium playing abrasive media function.Abrasive media is of a size of 400 μm, and volume is 50mL.The rotating speed of agitator is 3200rpm (~ 11.4m/s).Running temperature is less than 35 DEG C.

For preparing grinding suspension, all substrate being formed material and is dissolved in DI water, then under Strong shear mixing, add API powder.Shear-mixed continues 15 minutes, with complete wetting and the sample that homogenizes.According to the amount forming foam, sample is put into refrigerator a period of time, to reduce foam.Grinding in medium mill (media mill) also stirs 10 minutes again, until after dissolving completely, added by mannitol in API suspension.

At two time points: after namely just grinding, and after suspension being left standstill 2 days (2-d) under room temperature, with DI water dilute sample, afterwards, measure API nanoparticle size with laser diffraction (LS 13 320, Coulter Beckman).

Table 8-wet agitated medium grinding after API nanoparticle size

Embodiment 7

Present embodiment illustrates the method that the suitable substrate of qualification forms material and concentration thereof.At room temperature carry out all precipitation tests.FNB is dissolved in acetone or Et-OH, to form clear solution.By stirring, substrate is formed material and be dissolved in DI water.The concentration of polymer or surfactant changes between 10,25 and 50% (w/w) relative to FNV.During supersound process, drug solution is added aqueous phase fast.Sonication treatment time is 1 minute, comprises the initial solvent joining day.After precipitation, suspension is at room temperature stored 2 days.The suspension of sedimentation after 2 days is discarded, and prepares the suspension that still suspends for dimension analysis.Front in granularmetric analysis (sizing), in vortex mixer or magnetic stirrer, suspension is mixed 1 minute.Size up in laser diffraction Size Analyzer LS 13-320.Final drug level in suspension is 0.32% (w/v).

Embodiment 8

The use of the present embodiment card is T-shaped is mixed with API nano suspending liquid.Some materials used in the present embodiment and following embodiments are listed in table 9.

The material that table 9-T type is used in combination

Delrin (delrin) cylinder that T-shaped blender is multiplied by 2 inches long by 2 inches of ID (internal diameter) is made.Delrin cylinder is purchased from McMaster Carr (Santa Fe Springs, CA).In cylinder sides drill two holes, to become the input port of solvent resistant stream and solvent stream.The OD (external diameter) of two entrances is 0.0787 inch.Also the T-shaped blender delivery outlet of 0.1875 inch of OD is got out, for the output stream of precipitation suspension.Another hole of 0.5 inch diameter is got out, for ultrasound probe at the top of T-shaped blender.Use the ultrasound probe without special seal.The open design of T-shaped blender for conform to adaptive ultrasound probe, to guarantee optimum fluid-nozzle contact.

Use HPLC pump (Laballiance Model CP), with 16.5 ~ 17 and 55.1 ~ 52ml/min, organic solution and solvent resistant solution are pumped into T-shaped blender respectively.Fig. 5 depicts flow direction.Solvent resistant temperature is remained on 1 DEG C, and organic solution is room temperature.Find according to document, the reduction of solvent resistant temperature makes medicine equilbrium solubility in the solution decline, and which increases supersaturation amount.Along with oversaturated increase, nucleation rate improves, and particle diameter increases.Total lot amount size is 80ml.In 80ml suspension, 10ml is solvent, and 70ml is solvent resistant.Before precipitation, 20ml solvent resistant is put into collecting chamber and is used for quenching, all the other 50ml are pumped T-shaped blender.Collecting chamber is remained in ultra sonic bath, continual ultrasonic process during T-shaped combined experiments.After precipitation, with 25 μm of metre filter suspensions, with the bulk observed during removing precipitation.Suspension is at room temperature stored 2 days, and surveys particle diameter by laser diffraction.Final drug level in suspension is 0.32%, comprises loss of solids.

The FNB suspension using T-shaped blender to produce can be divided into three groups: the suspension of the suspension that completely stable suspension, moderate are stable and instability.Completely stable suspension does not show any particle diameter and increases after at room temperature storing 2 days.The particle diameter showing FNB in the stable suspension of moderate after its formation 10 minutes increases.Unstable suspension is reunited immediately.

The completely stable API nano suspending liquid of table 10-

The API nano suspending liquid that table 11-moderate is stable

Embodiment 9

In the present embodiment, in T-shaped mixing, the drug loading (FNB) in suspension becomes 4% (w/v) from 0.32% (w/v), thus proves the effect to stability of suspension.By suspension (behind 10 minutes and 2 days of T-shaped mixing) at Sorvall RC28S centrifuge (DupontInstruments-Sorvall Miami, FL) with 20000rpm centrifugal 0.5 hour, or with 10000rpm centrifugal 1 hour, to remove organic solvent from suspension.Discard the supernatant of large volume.In residue supernatant, with pipettor by mixing resuspension solid gently.By this way, the concentration of FNB is increased to 10 ~ 27% (w/v) from 1% ~ 4%.

Table 12 gives the stability result of suspension.

Table 12-drug loading and API nano suspending liquid stability

Several significant observed result is obtained by this embodiment.HPMC and P-68 can be used in T-shaped blender, to produce the drug loading up to 4% as substrate formation material and acetone as solvent.But the increase of drug loading causes API nanoparticle size to increase, because denseer suspension is more difficult to stablize (higher collision frequency).In addition, higher drug loading needs the substrate of higher concentration to form material, and this causes solvent-proof viscosity to increase.By centrifugal and resuspension, drug loading is increased to up to 27%, and particle diameter is without any significant change.

Embodiment 10

In the present embodiment, melting emulsification method is used to produce suspension.Fig. 4 shows melting emulsification method, and it relates to following steps:

1) micronized drug particles and stabilizing agent are scattered in water, and suspension is heated to the temperature of more than drug melting point.For guaranteeing to melt completely and reducing the viscosity of fused mass, use the temperature higher than drug melting point at least 10 DEG C.In heating process, stir gently with magnetic stirrer.

2) use ultrasound probe (Vibra Cell VC 750, Sonics & Materials, Inc., Newtown, CT) with the time different with varying strength emulsifying.In emulsifying step, under sample being remained on the temperature (10-15 DEG C+Tm) of rising, to avoid the solidification of fused mass.

3) hot emulsion is quickly cooled to the temperature of less than 10 DEG C in the temperature chamber (NESLAB TRE 10, Thermo Electron Corporation, Newington, NH) of 4 DEG C, causes drug particles to solidify.Final acquisition FNB nano suspending liquid.After cooling, measure particle size distribution by laser diffraction (LS-13320, Coulter Beckman).This embodiment uses the suspension of 50ml, and the wave amplitude of supersound process is at 100% (~ 95W).

The material that table 13-melting emulsifying is used

Stabilizing agent used	Be called for short	Function	Manufacturer
				Pluronic F-68	P68	Polymeric surfactant	Sigma Aldrich
Pluronic F-127	P127	Polymeric surfactant	Sigma Aldrich
				Polyoxyethylene Sorbitan Monooleate	Tween 80	Non-ionic surface active agent	Sigma Aldrich
Polyvinyl alcohol	PVA	Polymer	Sigma Aldrich
				PVP K30	PVP-K30	Polymer	Sigma Aldrich
Polyvinylpyrrolidone K360	PVP-K360	Polymer	Sigma Aldrich

Study based on the particle diameter after being formed and evaluate different stabilizing agents and stabilizer concentration.The stable needs of antagonism droplet coalescence and particle agglomeration obtains the drug particles within the scope of desired size.Fig. 9 shows API nanoparticle size.

Figure 10 shows when improving the drug loading of suspension, and it is on the impact of median particle diameter, as measured when surfactant P-127 exists.

Embodiment 11

In the present embodiment, fluidized bed coating process (FCB) is used to use API nano suspending liquid coated carrier granule.Device for the present embodiment is the MiniGlatt 9550 of band top jet nozzle.Atomizing pressure is 0.8-1.0bar.For PS, flow velocity is 1.4-1.6cfm; For CS and GranuLac 200, flow velocity is 0.8-1.2cfm; For Pharmatose, flow velocity is 3.4-3.6cfm.Spray rate is 0.25-1.5ml/min.Inlet temperature is remained on 68 DEG C.For PS/CS, maximum bed humidity is < 40%, is < 25% for lactose.The bed quality used is 150g.

Embodiment 12

In the present embodiment, a certain amount of mannitol (be 50% relative to FNB) and SDS (be 5% relative to FNB) are added in API nano suspending liquid, carries out fluidized bed coating process subsequently.In order to improve the stability of API nano suspending liquid, under low SDS concentration (be 0.75%SDS relative to FNB), carry out grinding steps.Just before API nano suspending liquid is put into FBC, the SDS of other major part and mannitol are added API nano suspending liquid.Homogenize API nano suspending liquid under shear-mixed, until two kinds of excipient are dissolved in disperse medium completely.

The carrier granular of dry method coating may be reunited during fluidized bed coating process.The present invention uses the reunion degree of reuniting than carrier granular during (AR) quantitatively fluidized bed coating process (FBC).It is defined as the area under the grading curve of the fluidized bed coating process granule after the area under the grading curve deducting the same granule measured before fluidized bed coating process step.Reunite than can such as be represented by the area A in Figure 36.

Table 14 gives the result using this kind of API nano suspending liquid.Table 14 Far Left one hurdle gives embodiment below reference substance used.

The fluidized bed coating process that table 14-uses the API nano suspending liquid adding SDS/ mannitol to carry out

* for L-91, larger carrier granular is employed.The distribution of sizes of starting vector material (pharmatose) is given in Figure 27.The fluidization granule of situation applied for dry method.

Figure 11 and Figure 12 A-12B gives the SEM image of two kinds of different composite powder.In fig. 11, potato starch (PS) granule of coating is shown.The surface of PS is covered with embedding API granular layer in the polymer matrix.PS granule can be used as independent granule use, its with record only 5.7% reunion than meeting well.Except PS granule, more visible thinner spherical spray-dried granules in some samples.

In Figure 12 A-12B, show the lactose granule of coating.In fig. 12, the pattern general view of sample is provided.The wide distribution of sizes of lactose and irregularly shaped clearly visible.The aggregate of carrier granular is also shown in sample.Figure 12 B is the nearer view of surface of lactose after fluidized bed coating process.The even coating layer be made up of the FNB granule of nano-scale surrounds lactose granule.The size of FNB granule well meets with the size recorded in nano suspending liquid, and this proves during spraying, obvious germination not to occur in fluid bed.

Embodiment 13

In the present embodiment, the impact of Polymer-supported on fluidized bed coating process (FBC) is demonstrated.During FBC, the reunion of carrier granular may be there is.In fig. 13, the reunion ratio of the function as Polymer-supported (being the HPMC from grinding suspension) is given here.Even if when not having carrier granular to reunite, also there is the minimum reunion ratio of about 5%, this is because the fine grained loss of the filter by FBC device causes, thus changes distribution of sizes into large-size.

More than restricted Polymer-supported, there is the reunion of carrier granular.Between reunion ratio and Polymer-supported, seem to there is linear dependence, as long as API nano suspending liquid has same concentrations.

Embodiment 14

In the present embodiment, the stability of the API nano suspending liquid after long term storage is tested.By API nano suspending liquid sample storage under freezing conditions (~ 8 DEG C).Only mix gently with pipettor, with the sample that homogenizes before granularmetric analysis.Change of size is listed in table 15.

The long-time stability of table 15-API nano suspending liquid

Embodiment 15

In the present embodiment, the stability of the API nano suspending liquid after adding mannitol and SDS is tested.API nano suspending liquid after grinding has 30%FNB, 10%HPMC and 0.75%SDS.After just grinding, 4.25%SDS and 50% mannitol are added API nano suspending liquid.As shown in figure 14, particle diameter increases slightly, and this may be that this is beneficial to Ostwald ripening and particle diameter subsequently increases because SDS content makes caused by the raising of FNB dissolubility.

Embodiment 16

The zooscopy of Canis familiaris L. is carried out with preparation PS-70 (loose powder and compressed tablet).Use the Catalent press ENTERPAC of band instrument NATOLI-12-02-3750, model: MTCM-1 prepares the tablet of preparation PS-70.Tablet diameter is 0.375 inch.Pressure is set to 2500psi, carries out about 2 seconds, so that composite powder is pressed into tablet.Tablet quality is 355mg, and this is equivalent to the FNB content of 48mg.Shown in Figure 15 in 6 Canis familiaris L.s one differentiation of merely hitting FNB plasma density.Three groups of this research are: 1) TriCore tablet (48mg, commercially available fenofibrate tablet), 2) PS-70 tablet, 3) loose powder.In all Canis familiaris L.s, viewed trend is identical.

The bioavailability of higher than micronization FNB 6 times of TriCore tablet display, preparation PS-70 shows the bioavailability of only twice, and this also depends on dosage form (tablet or loose powder) to lesser extent.

Embodiment 17

In dissolution test, demonstrate API discharge fast from API composite particles.Use Distek 2100C series, USP II (paddle board method) carries out dissolution test.Dissolution testing conditions is: background media is 25mM SDS solution; Container capacity is 900mL; Temperature 37 DEG C; Mixing speed changes from 0-100rpm; Sample size is ~ 48mg; Always meet sink conditions (dissolubility FNB/cFNB > 3).Use syringe manually sample acquisitions at stripping test period and sample afterwards, and carry out the filtration (filter size 0.45 μm) of sample immediately.By the medicament contg of spectrophotometer in the wavelength working sample of 290nm.This dissolution test step is also for embodiment 18-26.

Some use in the present embodiment and other embodiments are called for short: PS-potato starch, Bi-corn starch, L-lactose, LP-loose powder, T-tablet.

API composite particles using potato starch as carrier demonstrates stripping curve as shown in figure 16.PS-70-T demonstrates Fast Stripping, at 50rpm poor-performing when higher mixing speed (100rpm).

Embodiment 18

This example demonstrated the impact of coated polymer on dissolution test.As shown in figure 17.Composite powder containing PVP is slightly slower than the dissolution rate of the composite powder containing HPMC.Reason is, compared with HPMC preparation, the nano-particle in grinding suspension is not very stable.Therefore, FNB agglomerate grain the dissolution rate that slows down.

Embodiment 19

This example demonstrated the impact of size on Dissolution of Tablet of API nano-particle.Tablet is obtained by the different FNB composite powder tablettings of the FNB nano-particle comprising different size.The compression pressure of tablet is 108MPa, and the dwell time is 3 minutes.The diameter of tablet is 1/2 inch, and quality is ~ 220mg.Stir speed (S.S.) in stripping experiment is set as that 100rpm is to eliminate caking impact.

Stripping result is shown in Figure 18.Less API nanoparticle size causes faster stripping.

Embodiment 20

The present embodiment compares the stripping curve of griseofulvin (GF) and ibuprofen (Ibu) composite particles.This step of the present invention is for generating GF composite particles and Ibu composite particles.More specifically, GF composite particles uses following condition to obtain: GF nano suspending liquid contains 20%GF, 5%HPMC and 0.75%SDS.Milling time is 1 hour, produces the nano-particle with d50=219nm and d90=460nm.Carrier granular is the potato starch with the coating of M5P dry method.The reunion rate of API nano-particle is 8%.Dissolution medium is 18.7mM SDS solution.

Ibu composite particles uses following condition to obtain: Ibu nano suspending liquid contains 20%GF, 5%HPMC and 0.75%SDS.Milling time is 2 hours, produces the nano-particle with d50=303nm and d90=484nm.Carrier granular is the potato starch with the coating of M5P dry method.The reunion rate of API nano-particle is 10.2%.Dissolution medium is the phosphate buffer of pH 7.2.

For both of these case, stir speed (S.S.) is 100rpm, and powder quality is ~ 220mg.Stripping curve is shown in Figure 19, and wherein stripping curve is normalized to 100%.

Embodiment 21

The present embodiment compares the stripping curve using PS or CS as the FNB composite particles of carrier granular.Stir speed (S.S.) is 50rpm.This stripping curve in fig. 20.The API composite particles with corn starch has the relatively large nano-particle be dispersed in stripping container.This is because CS compares caused by the less particle diameter of PS and lower density, it reduces the impact of gravity on granule.Therefore, lump much smaller and reduce the impact of " capturing " medicine, but not eliminating completely.

Embodiment 22

The present embodiment compares the stripping curve of the FNB composite particles using different dry method coating material M5P (1.2%, hydrophilic, L-86) and R972P (1.85%, hydrophobic, L-85).Stir speed (S.S.) is 50rpm.This stripping curve provides in figure 21.The character of dry method coating material can not affect stripping curve significantly.Although the stripping of lactose can be slow a lot of when being coated with hydrophobic silica, the API-polymeric layer of outside is unaffected, and demonstrates the dissolved corrosion similar to other dry method coating materials.

Embodiment 23

The present embodiment compares the stripping curve of the FNB composite particles of the 0.01M HCl solution (PH ~ 2) using different dissolution medium 25mM SDS solution and have 25mM SDS.Stripping curve provides in fig. 22.The reduction of pH value does not affect dissolved corrosion.Thus this result is to expect because FNB is non-ionic compound.First sample point fluctuated after 1 minute, because powder is not also evenly distributed in stripping container.

Embodiment 24

The present embodiment compares the stripping curve using the FNB composite particles forming material without the polymer 10% of concentration and 25%HPMC as substrate.FNB composite particles L-88 uses spray suspension liquid herein: 25%HPMC, 5%SDS; And FNB composite particles L-93 uses spray suspension liquid: 10%HPMC, 5%SDS.Stripping curve provides in fig 23.Higher Polymer-supported has slowed down dissolution rate.Need the thicker polymeric film of long period stripping and discharge API nano-particle.

Embodiment 25

This example demonstrated the impact of mannitol on the stripping curve of FNB composite particles.Stripping curve provides in fig. 24.There is mannitol or be similar without the stripping curve of mannitol.But this may be because the preparation (L-93) without mannitol has demonstrated instantaneously stripping due to its high SDS content (5%) and low polymer content (10%).

Embodiment 26

This example demonstrated the impact of support particles sizes on the stripping curve of FNB composite particles.The carrier granular of two types is: Pharmatose:d10=43.7 μm, d50=112.0 μm, d90=198.1 μm; With GranuLac 200:d10=4.2 μm, d50=28.9 μm, d90=99.3 μm.Stripping curve is shown in Figure 25.Large and between tiny carrier granular stripping curve is similar.But the API composite particles with tiny support particles sizes demonstrates better redispersion performance.

Embodiment 27

This example demonstrated the uniformity of API composite particles (L-89).L-89 composite particles is divided into two kinds of grades: fine fraction: x < 45 μm; Coarse fraction: x > 90 μm.The particle size distribution of fine fraction and coarse fraction L-89 composite particles is shown in Figure 26.Fine fraction is distributed as: x10=9.2 μm, x50=30.9 μm, x90=59.7 μm.Coarse fraction is distributed as: x10=63.5 μm, x50=117.3 μm, x90=172.1 μm.Fine fraction and coarsely graded stripping curve are all shown in Figure 27.

Embodiment 28

This example demonstrated the redispersion behavior of the API nano-particle from API composite particles.The carrier granular that the present embodiment uses is lactose base, because it is water miscible.100mg API composite particles is dispersed in 8ml DI water.Bottle was stirred lightly in 30 seconds by hand moving.Then bottle is left standstill 2 minutes.By the size of laser diffraction measurement granule.Dispersion results is shown in Table 16.

The dispersion of table 16-API composite particles

Far better for the redispersibility in the SDS background solution of dissolution test.The complete redispersion realizing nano-particle needs high-caliber SDS and higher HPMC or mannitol content.In addition, larger carrier granular demonstrates poor redispersibility.FNB particle size distribution after API composite particles distributes is shown in Figure 28.The SEM image of discrete particles is shown in Figure 29 A-29B.

Embodiment 29

Some API composite powders (granule) are pressed into tablet.With card not (Carver) hydraulic press (model: 3851-0, Carver Inc.) carry out tabletting.Pill shapes is the cylindrical of surfacing; Tablet diameter is 1/2 inch.The slaking test of tablet is undertaken by being placed on by tablet in dusting cover (screen size 2mm), and wherein dusting cover is placed on the top of the beaker filling water.Beaker is placed on magnetic stirrer, measures to the last a part of tablet and pass the time of sieve.

Make API composite particles L-89 and different excipient as polyvinylpolypyrrolidone (CP), microcrystalline Cellulose (MCC) and magnesium stearate (MgSt) hand mix.Tablet size is ~ 310mg.The jitter time of these tablets is shown in Table 17.

The jitter time of table 17-FNB tablet

Study disintegrate and the dissolved corrosion of different API composite powder.Tabletting conditions is: the compression pressure of 77.4MPa (load: 1t), 2 seconds dwell times, and tablet quality is ~ 310mg.Result provides in table 18.

The disintegrate of the different API composite powder of table 18-and dissolved corrosion

The stripping curve of these API composite particles is shown in Figure 30.

Embodiment 30

In the present embodiment, different dry method painting methods is compared.Research dry method coated carrier granule is to determine whether they can fluidisations.Result provides in table 19.

The carrier granular of the dry method coating of the fluidity raising of table 19-

Embodiment 31

In the present embodiment, have studied the change in size of carrier granular after fluidized bed coating process.The corn starch applied dry method with fenofibrate nanometer suspension, potato starch and lactose carry out fluidized bed coating process, fenofibrate nanometer suspension be containing 20% or 30%FNB, the 5%HPMC relative to API, the 0.75%SLS relative to API agitated medium grinding in obtained.Result is shown in Table 20.

Change of size after table 20-fluidized bed coating process

Embodiment 32

In the present embodiment, have studied the change in size of the carrier granular after fluidized bed coating process.The corn starch applied dry method with fenofibrate nanometer suspension, potato starch and lactose carry out fluidized bed coating process, and fenofibrate nanometer suspension is prepared in containing the agitated medium grinding of 20%FNB, the 5%HPMC relative to API, the 0.75%SLS relative to API.Result is shown in table 21.

Size results shows, and lactose can with 20% and 30% fenofibrate nanometer suspension spray, and without significant change on agglomerate size.These high concentrations show to spray high drug load and to have no adverse effects, and this can cause the processing time of grinding and fluidized bed coating process significantly to shorten.

Change of size after table 21-fluidized bed coating process

Embodiment 33

In the present embodiment, with fenofibrate nanometer suspension, fluidized bed coating process is carried out to dry-coated lactose, potato starch and the corn starch covered.Analyze the powder sample of fluidized bed coating process in acetone, to characterize the uniformity of dosage units relevant to various different carriers granule.Result is shown in Table 22.The composite particles can observing fluidized bed coating process has good uniformity of dosage units.

Change of size after table 22-fluidized bed coating process

Embodiment 34

In the present embodiment, test has the stripping curve of the API composite particles of different carrier granular PS and CS, and result is shown in Figure 31.Compare the situation of potato starch, the small size of corn starch granules and high surface allow fenofibrate particles stripping quickly.

Embodiment 35

In the present embodiment, before fluidized bed coating process, mannitol is added in API nano suspending liquid.Mannitol can improve the initial stripping of fenofibrate as matrix formers and prevent incomplete stripping.The stripping curve of API composite particles is shown in Figure 32.When corn starch and potato starch are all used as carrier granular, the existence of mannitol significantly can improve the stripping of composite particles.Under mannitol exists, from corn starch carrier granular, stripping fenofibrate allows fenofibrate stripping completely in less than 1 minute.

Embodiment 36

In the present embodiment, by containing the fenofibrate nanometer suspension of mannitol by fluidized bed coating process on lactose and potato starch particle, to observe by using tiny, solvable carrier granular whether can improve stripping property.Coated conditions is listed in table 23.

Table 23-uses the fluidized bed coating process of different carriers granule

Stripping result shows that water-solubility carrier can improve the stripping of fenofibrate from composite particles really.Figure 33.Lactose (28mm) and potato starch (35mm) granule show suitable stripping curve in early days.Water solublity lactose granule does not lump at stripping container bottom, and is able to complete stripping.

Embodiment 37

In the present embodiment, compare the fenofibrate nanometer suspension prepared by distinct methods, to determine their impacts on the stripping curve of the lactose with FNB suspension fluidized bed coating process, described FNB suspension is by following preparation:

Agitated medium grinds: L-88:20%FNB, 25%HPMC, 5%SDS ~ 160nm;

Agitated medium grinds: L-89:30%FNB, 10%HPMC, 5%SDS, 50% mannitol ~ 160nm;

LASP:L-94:14.8%FNB, 19.2%HPMC, 7.7%SDS, 50% mannitol; D50 ~ 3 μm.

The stripping curve of the FNB composite particles obtained is shown in Figure 34.Even if stripping result shows at LASP (1-94, fenofibrate particles 3mm) produced in technique grinds (1-88/1-89 much larger than by agitated medium, fenofibrate particles 0.16mm) produced, the fenofibrate of 85% still stripping in less than 5 minutes.Stripping result shows that the high polymer concentration needed for LASP limits the stripping of fenofibrate.

Embodiment 38

In the present embodiment, have studied the impact of LASP preparation on FNB composite particles (lactose carrier) stripping.Employ two kinds of LASP preparations:

Preparation 1:L-92:9.3%FNB, 25%HPMC, 50%P-68; D50 ~ 1.1 μm;

Preparation 2:14.8%FNB, 19.2%HPMC, 7.7%SDS, 50% mannitol; D50 ~ 3 μm.

The stripping curve of API composite particles is shown in Figure 35.Even if use P-68 to cause obviously less granule, this polymeric surfactant still significantly can slow down the stripping of fenofibrate in API composite particles.

Embodiment 39

In the present embodiment, the dry method of lactose granule (GranuLac200) is coated in resonance mixed instrument LabRAM and carries out.Host grain and objective particle packing are entered in mixing chamber and does not carry out any premixing.The powder that total lot amount size is 150g is processed in mixed instrument.This quality makes the fill level in 500ml agitator tank be about 50%.Summarize in table 24 different silicon dioxide carried under process conditions and the FFC of gained.

The mobility of GranuLac 200 before and after the coating of table 24-dry method

The increase mobility observed with dioxide-containing silica improves.The fluidisation of lactose granule is allowed with the coating of 1% and 1.5%M5P.Under the M5P of 1% content, the SAC of 350% can be reached in theory; And under 1.5%M5P, the SAC of 530% can be reached in theory.Irregularly shaped and the wide distribution of sizes of GranuLac 200 limits the improvement of mobility.

Embodiment 40

In the present embodiment, the Star using TGA/DSC1 namely to have nitrogen to purge ^esystem (Mettler-Toledo, Columbus, OH) measures the water content of complex by thermogravimetry.With the constant rate of speed of 10 DEG C/min, sample is heated to 110 DEG C.Calculate the percent weight loss due to moisture evaporation subsequently, and be defined as water content.The water content of the complex of fluidized bed coating process is summarized in table 25.

The water content of the complex of table 25-fluidized bed coating process

Compared to other complex, there is the water content of the complex of lactose carrier low.Have that to cause compared with the method for low water content and material be favourable.The quality of medicine, hardness, compactness and pot-life depend on water content to a great extent.High-moisture can cause the problem of adhesion, mobility and poor stability.If the water content of complex is high, then the water content of the tablet obtained by this complex equally can be high.In the presence of moisture, solid dosage forms may lose its color or physical integrity.Sometimes, if the water content of tablet is high, then the excipient in tablet can serve as the Nutrient medium of growth of microorganism.If water content is too low, then may cause capping/layering and/or tablet coarse.

Embodiment 41

In the present embodiment, tablet is obtained by the complex without extra excipient.The composite that this example demonstrates by utilizing claimed method to be formed easily forms tablet; And set forth their exemplary performance.Use blocks not hydraulic press (model: 3851-0, Carver Inc.) tabletting.Pill shapes is the cylindrical of surfacing; Tablet diameter is 1/2 inch.Dwell time is 2 seconds.Use the load (77.4MPa and 38.7MPa) that two kinds different.Measure disintegration time and carry out stripping.The slaking test of tablet is undertaken by being placed on by tablet in dusting cover (screen size 2mm), and wherein dusting cover is placed on the top of the beaker that 600ml deionization (DI) water is housed.This beaker is placed on magnetic stirrer, measures to the last a part of tablet and pass the time of sieve.Measure the disintegration time of the tablet of different composite thing, and provide in table 26.In USP II, carry out the stripping of tablet, and SDS solution is used as dissolution medium.Filter used is of a size of 0.45 μm.The stripping of the tablet obtained by different composite powder is compared and is shown in Figure 37.

The disintegration time of the tablet that table 26-is obtained by the complex of the fluidized bed coating process of different carriers

The disintegration time of lactose tablet can be improved further, to make them and to form the stripping property of initial composite powder before tablet suitable.PS & CS is better than lactose (Figure 37) in the short disintegration time of first ten minutes period.But, after this, from complex, discharge nano-particle sooner occupy an leading position.Extra surfactant causes drug particles release (relative to 0.75% of CS & PS complex, sample L-89 has the surfactant of 5%) faster.In addition, at water-solubility carrier as in lactose, sample L-89 does not have agglomeration problems, but lumps when PS & CS.

Embodiment 42

In the present embodiment, tablet is obtained by lactose complex.Use extra granular super-disintegrant powder to improve disintegration time.The superdisintegrant agent concentration used or the amount of super-disintegrant are optimum.In USP II, carry out tablet stripping, and SDS solution is used as dissolution medium.The stripping of the tablet of different composite powder is compared and is shown in Figure 38 A.Compare by the obtained stripping curve of tablet of complex (sample L-87b & L-89) and the stripping curve of existing commercially available Tricor tablet.This compares and is shown in Figure 38 B.

The tablet obtained by the L-87b complex containing CCS (1%) has better stripping property than the tablet obtained by L-89 complex.For the tablet that L-87b complex is obtained, the medicine of about 80% is less than the time stripping of 10 minutes.The stripping property of the tablet using CCS to be obtained by L-89 complex does not improve.The tablet obtained by the L-87b complex containing 1%CCS is suitable with the stripping property of Tricor tablet.

Embodiment 43

In the present embodiment, tablet is obtained by L-87b and CS-96 complex.The complex containing 1%CCS and 6.25%SDS (relative to FNB) is used to obtain tablet.Extra SDS does not comprise in the composite, but is joined in mixture before making tablet.Extra SDS makes total SDS concentration be 7% (relative to FNB), and it is identical with Tricor tablet.The relatively stripping of this tablet and commercially available Tricor tablet.Dissolution medium is the 0.01M sodium phosphate buffer containing 10mM SDS.The stripping curve of more all three kinds of tablets is also shown in Figure 39.The stripping property of the tablet obtained by L-87b complex and Tricor tablet is suitable.Particularly, the dissolution rate of the tablet obtained by L-87b complex after 20 minutes dissolution times is more favourable.

Embodiment 44

In the present embodiment, the hardness of the tablet obtained by complex is measured.In first, tablet is obtained by the nano composite powder not adding any excipient.Tablet weight is in the scope of 328-418mg (~ 48mg FNB).Use block not pressure mechanism for tablet.Dwell time is 2 seconds.Dr.Schleuniger (Model-6D) hardness tester is used to test.Test result is summarised in table 27.In second batch, prepare tablet by 1%Mg-St and 1%CCS is added nano composite powder.The load applied in tableting processes is 38.7MPa.These test results are summarised in table 28.

The hardness of the tablet that table 27-obtains without the different composite thing of additional excipients

Table 28-is by the hardness of the tablet having the complex of excipient to obtain

Data from table 27 can be observed, and lower compression load causes the hardness of tablet less.For all complex, find similar observed result.PS complex has minimum tablet hardness.This effect is observed equally in slaking test.PS tablet has the shortest disintegration time.In complex, add excipient reduce further tablet hardness, except the tablet (table 28) obtained by L-87b complex.

Embodiment 45

In the present embodiment, in order to check the palliating degradation degree that between the storage life, nano-complex may experience, the degraded of the tablet obtained by L-87b complex is tested.Test the degraded that the tablet obtained by L-87b complex at room temperature stores a period of time.These tablets be equally use block not forcing press obtain.Tabletting is identical with embodiment 44 with leaching condition.Dissolution medium is 25mM SDS solution.Compared with initial stripping curve, according to the degraded inspection of the change storing rear stripping curve being assessed to tablet, and these results are shown in Figure 40.As shown in the figure, the difference of the dissolved corrosion after 10 days and 55 days is not observed.Therefore, these nano composite powders do not show any degraded in tablets.

Embodiment 46

In the present embodiment, the stripping property of the capsule of filling lactose complex is detected.The gelatine capsule of " 0 " specification is used for this object.The composite powder that capsule is equipped with is equivalent to 48mg FNB dosage.Each capsule hand-filling.Dissolution test is completed in USP II.Capsule stripping uses the 40 order baskets having adapter.Mixing speed maintains 50rpm (suitable with tablet dissolution test) and 100rpm (general in the literature).Dissolution medium used is 25mM SDS solution.Other operating conditions and above-mentioned tablet dissolution test are consistent.Stripping curve is shown in Figure 41.

When using the mixing speed of 50rpm, find that the capsule stripping obtained is slower than tablet stripping.But when using the mixing speed of 100rpm, capsule stripping improves relative to tablet stripping.Observe the basal surface that glue shell fragment is stuck in adapter, prevent powder stripping thus, thus disturb the potential stripping of nano composite powder.

Should understand, although many Characteristics and advantages of the present invention describe above together with 26S Proteasome Structure and Function details of the present invention, but these disclosures are only illustrative, and in the principle of the present invention of the integrated degree indicated by the broad sense of the term of claim expression of enclosing, particularly can change in the shape of parts, size and layout details.

Claims (35)

1. a composite particles, it comprises:

Core; And

Skin, the nano-particle and at least one substrate that comprise Absorbable rod material form material.

2. composite particles as claimed in claim 1, wherein said core to be median particle size range the be granule of about 20 μMs to about 200 μMs.

3. composite particles as claimed in claim 1, wherein said core comprises the material being selected from starch, lactose, sucrose, cellulose, cellulose ethers and composition thereof.

4. composite particles as claimed in claim 1, also comprises the fluidised material layer between described core and described skin.

5. composite particles as claimed in claim 4, wherein said fluidised material is selected from silicon dioxide, aluminium oxide, titanium dioxide, white carbon black, calcium aluminosilicate, calcium silicates, magnesium silicate, potassium silicate, sodium silicate, sodium aluminosilicate, sodium aluminosilicate calcium, tricalcium silicate, aerosil, Talcum, ferrum oxide, other metal-oxides and composition thereof.

6. composite particles as claimed in claim 4, the dispersion surface energy of wherein said fluidised material is less than 60mJ/m ²and its median particle diameter is 5nm to 100nm.

7. composite particles as claimed in claim 6, wherein said fluidised material comprises nano SiO 2 particle.

8. composite particles as claimed in claim 1, wherein said Absorbable rod material comprises at least one medicinal active ingredient that scope is 0.01-50wt%.

9. composite particles as claimed in claim 9, the size range of wherein said Absorbable rod material grains is about 10nm to about 1000nm.

10. composite particles as claimed in claim 9, the size range of wherein said Absorbable rod material grains is about 10nm to about 200nm.

11. composite particles as claimed in claim 1, wherein said substrate forms material and comprises at least one polymer.

12. medicinal composite particles as claimed in claim 12, wherein said at least one polymer is selected from hydroxypropyl cellulose, hydroxypropyl emthylcellulose, poly-(vinyl alcohol), PVP, ammonio methacrylate copolymer, ethyl cellulose, hydroxy methocel, hydroxyethyl-cellulose, methylcellulose, sanlose, arabic gum and combination thereof.

13. composite particles as claimed in claim 12, wherein at least one surfactant is selected from sodium lauryl sulphate, dioctylsulfosuccinat, ethylene oxide/propylene oxide copolymer, cetab, polysorbate esters, sodium alginate, lecithin, sodium laurylsulfate, monoleate, monolaurate, monostearate, stearyl alcohol, octadecanol, alevaire, GREMAPHOR GS32 and composition thereof.

14. methods preparing composite particles, it comprises the following steps:

Prepare the nano-particle of Absorbable rod material and the suspension of at least one substrate formation material; And

Described suspension fluid bed is coated on carrier granular.

15. methods as claimed in claim 14, the median particle size range of wherein said carrier granular is about 20 μMs to about 200 μMs.

16. methods as claimed in claim 15, wherein said carrier granular comprises the material being selected from starch, lactose, sucrose, cellulose, cellulose derivative and composition thereof.

17. methods as claimed in claim 15, the median particle size range of wherein said nano-particle is 5nm to 100nm.

18. methods as claimed in claim 15, wherein said nano-particle material is selected from silicon dioxide, aluminium oxide, titanium dioxide, white carbon black, calcium aluminosilicate, calcium silicates, magnesium silicate, potassium silicate, sodium silicate, sodium aluminosilicate, sodium aluminosilicate calcium, tricalcium silicate, aerosil, Talcum, ferrum oxide, other metal-oxides and composition thereof.

19. methods as claimed in claim 15, apply the step of described carrier material by fluidised material dry method before being also included in described fluidized bed coating process step.

20. methods as claimed in claim 19, wherein said dry method coating is carried out being enough to make the surface area coverage of described carrier material reach the time of 35% to about 100%.

21. methods as claimed in claim 20, wherein said fluidised material is 0.1% to 10% of described fluidised material and carrier material gross weight.

22. methods as claimed in claim 15, wherein said Absorbable rod material comprises at least one medicinal active ingredient.

23. methods as claimed in claim 22, wherein said medicinal active ingredient is the 5%w/v% to 50w/v% of described suspension gross weight.

24. methods as claimed in claim 22, the size range of the granule wherein containing described medicinal active ingredient is about 10nm to about 1000nm.

25. methods as claimed in claim 22, the solvent wherein for described suspension is selected from the tert-butyl alcohol (TBA), oxolane (THF), dimethyl sulfoxine (DMSO), dichloromethane, dimethyl formamide (DMF), methanol and composition thereof.

26. methods as claimed in claim 22, the solvent wherein for described suspension comprises water.

27. methods as claimed in claim 26, wherein said suspension comprises at least one substrate and forms material and surfactant.

28. methods as claimed in claim 22, wherein said at least one substrate forms material and comprises polymer.

29. methods as claimed in claim 28, wherein said polymer is selected from hydroxypropyl cellulose, hydroxypropyl emthylcellulose, poly-(vinyl alcohol), PVP, PVP-K360, PVP-K30, ammonio methacrylate copolymer, ethyl cellulose and combination thereof.

30. methods as claimed in claim 28, wherein said suspension also comprises non-ionic surface active agent.

31. methods as claimed in claim 28, wherein said surfactant is selected from sodium lauryl sulphate, dioctylsulfosuccinat, PLURONICS F87, cetab, poloxamer188, polysorbate, sodium alginate.

32. methods as claimed in claim 22, wherein said at least one substrate forms the nano suspending liquid that material comprises 5w/v%-50w/v%.

33. methods as claimed in claim 15, the wherein said fluidized bed coating process step scope of application is the fluidizing velocity of 1cm/s-10cm/s.

34. methods as claimed in claim 15, the wherein said fluidized bed coating process step scope of application is the fluidisation flow velocity of 0.1cfm-5cfm.

35. methods as claimed in claim 15, the wherein said fluidized bed coating process step scope of application is that the atomizing pressure of 5psig-35psig is to be atomized described suspension.